Keto-sulfones



Patented June 10, 1947 UNITED STATES PATENT'QFF'I'CE KETO-SULFONES Moses-WolfGoldbcrg; Montclair, N. J..,..assignor to Hoffmann -Il'a Roche, Inc.,. Roche. Park,. Nutley, N; vJ acorporationof New Jersey NoD'irawing, ApplicationiAugnstilfi, 19.44, SerialNo. 549,797

trated by the general'formul'al R2 R s-( i-cH-'co-R wherein R stands for an amino radical or a nitrogen-containing. radical convertibleinto. an amino radical, such as nitro or acylamino radicals, COR is an acyl radical, in which R may stand for a hydrocarbon radical such as one selected from the group consisting of alkyl, cycloalkyl, alkenyl, aryl, aralkyl, and aralkenyl radicals, and R R3, and R each may. stand for hydrogen or a hydrocarbon radical. such as, a radical. selected from the group consisting of alkyl cycloalkyl, alkenyl, aryLaraIkyl;.andlaralkenyl, specific examples of the. radicals. being methyl, ethyl, higher alkyl, cyclopentyl, cyclohexyl, cyclohexenyl, propenyl; butenyl; phenyl, p-tolyl, p-chlorophenyL' naphthyl, .benzyhplienylethyl, and. phenylethenyl.

Dissymmetric sulfones of this type have notryet been described. Furthermore, compounds of'this general type have never been investigatedas to their possible therapeutic usefulness. It was therefore surprising to findthat these keto-sul- 30 fones represent a new type of useful intestinal antiseptics, being in this respect superior to the known compounds ofthe sulfanilamide series. They are practically atoxic, and they are not resorbed from the intestinal-tract. When doses as high as 5 grams per' kilogram of the new sulfoneswith a free amino group in the phenyl radical are fed to" mice, not a-trace of diazot'abl'e substances can be found in the bloodof the animals.

Thus, for example, p-aminophenyl-(l-phenyl- 2-benzoyl-ethyD-sulfone, one of the compounds described in the attached examples, was tolerated by'mice Without any toxic symptoms-in amounts exceeding grams per: kilogram when-administered orally. No lethal or toxic dose could be reached. When normal mice were kept on a diet containing 1% of this new compound; a very substantial decrease in the count oi coliforme organisms was found in at'- least 80% of the fecal specimens ofthe'treated' animals.

These new compounds can be prepared by reacting p-amino-benzene-sulfinic' acid, or a similar benzene-sulfinic acid. derivative substituted in para-position by a nitrogen-containing" radical 557 convertible into an amino, radical, for. example, p-nitro-benzene-sulfinic acid orp-acetaminobenzene-sulfinic. acid, with an unsaturatedketone; containing at least one doublebondnin. a,p-posi.--

tion tothe ketogroup; This methochhas beenfound to be of general applicability, and permitsa very wide variation in the constitution of the new compounds; by using various w,punsaturated? ketones. The reaction can be performed by heating the components iniaqueous alcohol, or a similar suitable solvent or diluent, whereby the new keto-sulfones are obtained" in good" yields." In accordance with the general rules governing addition reactions to the double bond of c p-unsaturated ketonesyitisto ber. assumed'i that in this' reaction the sulfur atom" ofthe sulfinic acid is probably linked with the B-carbon atom of the cab-unsaturated ketone.

Thus, for example, byreacting p-amino-benzene-sulfinic acid with benzal-acetone, p-aminophenyll-phenyl-Z-acetyl-ethyl) sulfone is obtainedin yield; The same compoundican also... be prepared by. reacting p-nitro-benzenesulfinic-acid-with benzal-acetone, and reducing. the nitro-group in the p-nitro-phenyle (1-phenyl--- Z-acetyhethylM-sulfone thus formed, or by reacting. p-acetamino-benzene-sulfinicacid with: benzal-acetone to form p-acetamino-phenyl-(L phenyl-z-acetyl-ethyl)-su1fone, and saponifying the acetamino-grouplin this intermediatea. In a similar manner p-amino-phenyl-(1-phenyl 2 benzoyl-ethyD-sulfone is. obtained by reacting p-amino-benzene-sulflnic acid'with benzal-acetophenone.

The following; examples illustrate the invention:

EXAMPLE 1 HzN Calc; for C H O NS: C Found: 0

EXAMPLE 2 p-Amino-phenyl- (1-phenyZ-2-acetyl-ethyl) sulfone A mixture of 225 g. of p-amino-benzene-sulfinic acid and 265 g. of benzal-acetone in 3 liters of 80% ethyl alcohol is refluxed for 4 hours. The mixture, which contains large amounts of the insoluble reaction product, is filtered with suction while hot. The precipitate is washed on the filter with dilute and absolute ethyl alcohol, and thoroughly dried in vacuo. 315 g. of the sulfone are thus obtained, corresponding to a yield of 80.5% of the theory. The product melts at 179-181 C. with decomposition. Upon recrystallization from dioxane-water (1:1), with the addition of activated carbon, an absolutely white preparation is obtained, melting with decomposition at 1'79 181 C.

Calc. for CmHuOaNSZ c 63.34 H 5.65 N 4.62% Found: 63.36 H 5.42 N 4.63%

EXAMPLE 3 p-Nz'tro-phenyl- (1 -phenyZ-2-acetyl-ethyl) sulfone 5 g. p-nitro-benzene-sulfinic acid and 5 g. benzal-acetone are mixed in 200 cc. 70% ethyl alcohol. On warming a clear yellow solution is obtained, which is refluxed for 90 minutes. On standing overnight at room temperature colorless crystals appear. They are filtered off, and twice recrystallized from 70% alcohol. Yield 9.0 g. M. P. 125-126 C.

Calc. for CH15O5NS: c 57.73 H 4.80% Found 0 57.65 H 4.53%

EXAMPLE 4 Catalytic reduction of p-m'tro-phenyZ-(l -phenyl- Z-acetyZ-ethyl) -sulfone 0.5 g. of this nitro-sulfone described in Example 3 are catalytically reduced in 50 cc. absolute ethyl alcohol in the presence of 0.2 g. platinum oxide catalyst. At 25 C., and an initial hydrogen pressure of 30 pounds, a very rapid hydrogen absorption occurs. The reduced product precipitates as the reaction proceeds. When the theoretical amount of hydrogen is absorbed, 200 cc. acetone are added, to dissolve the precipitated amino-sulfone. The platinum is then filtered off, and the filtrate concentrated in vacuo to dryness. The colorless solid residue is recrystallized from a 1:1 dioxane-water mixture, washed with Water and dried. 0.3 g. colorless needles are obtained, melting at 179-181 C. The reduction product is identical with the p-amino-phenyl-(1-phenyl-2-acetyl-ethyl) -sulfone described in Example 2. The two samples show no melting point depression when mixed.

EXAMPLE 5 p-Acetamino-phenyl-(1-phenyZ-2-acetyl-ethyl) sulfone 1 g. benzal-acetone and 1 g. p-acetamino-benzene-sulfinic acid are refluxed for 1 hour in 50 cc. ethyl alcohol. The solution is then concentrated to 5 cc., and water is added until it becomes turbid. On cooling colorless crystals are formed, which are purified by recrystallization from aqueous alcohol. Yield 1.2 g. M. P. 162163 C., with decomposition.

Calc. for CmHwoiNSz C 62.61 Found: 0 62.59

H 5 N 4.06% H 5.62

On saponification with a 5% sodium carbonate solution in aqueous alcohol the N-acetyl-group is split off, and p-amino-phenyl-(l-phenyl-Z-acetyl-ethyl -sulf0ne is formed.

EXAMPLE 6 p-Amino-phenyl- (1 -phenyl-2-benz0yl-ethyl) sulfone Calc. for CQlHmOaNS: C 69.04 H 5.21% Found: 0 69.08 H 4.94%

EXAMPLE '7 p-Amino-phenyl- (1 -phenyZ-2-cinnamoyl-ethyl) sulfone H2N s02( 3H-omoo-o11=oH 32 g. of dibenzal-acetone and 16 g. of p-aminobenzene-sulfinic acid are refluxed in 300 cc. ethyl alcohol for 5 hours. The voluminous reaction product is filtered with suction, and is washed with 80% and with absolute alcohol. It is then suspended in acetone with stirring, and allowed to settle. The acetone is then decanted. This is repeated several times, and the precipitate then dried in vacuo. The pale yellow product thus obtained is completely insoluble in all the common organic solvents. Yield 38 g. M. P. 210-212 C., with decomposition.

The acetone-Washed product is pure, and gives good analytical results.

Calc. for CzaHmOaNSZ C 70.59 H 5.37% Found: C 70.49 H 5.40%

R3 R4 wherein R is amino, COR is an acyl radical in which R is a hydrocarbon radical, and R R and R each stands for a member of the group consisting of hydrocarbon radicals and hydrogen 2. p -Amino-phenyl-(l-phenyl-Z benzoyl-ethyl) -sulfone.

3. p-Amino-phenyll-phenyl-2-acetyl-ethyl) sulfqne.

4. p Amino phenyl -(1-phenyl-2-cinnamoy1- ethyl) -sulfone.

MOSES IVOLF GOLDBERG.

CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS 10 Number Name Date 2,010,828 Rothrock Aug. 13, 1935 2,207,021 Martin et a1, July 9, 1940 FOREIGN PATENTS 15 Number Country Date 508,148 Great Britain June 2'7, 1939 

